Pyrazinoic acid esters have been synthesized and found to have greater intrinsic activity against pyrazinamide-susceptible and pyrazinamide-resistant isolates of M. tuberculosis. These compounds have intrinsic activity against M. bovis and M. kansasii, organisms which are resistant to pyrazinamide. The pyrazinoic acid esters and pyrazinamide function as prodrugs of pyrazinoic acids. The former agents require a mycobacterial esterase for activation rather than an amidase which is required by the latter agent. The in vitro and in vivo activity of PAEs will be optimized by modification of both the alcohol and pyrazine moieties. New analogs will be evaluated in vitro and in M. tuberculosis infected murine macrophage cultures. The toxicity and pharmacology of selected PAEs will be studied prior to their evaluation in a murine tuberculosis model. The development of additional agents for,the treatment of tuberculosis is of great importance due to the emergence of multidrug resistant tuberculosis in HIV infected individuals (particularly prisoners and intravenous drug users). Rational structural modification of a well established primary agent such as pyrazinamide has a high likelihood of yielding a new candidate for clinical evaluation.